Emerging evidence supports the hypothesis that the skeleton is also an endocrine organ that regulates energy metabolism through the release of the osteoblast-derived hormone, osteocalcin (Ocn). This novel hypothesis is controversial, because important gaps remain to be filled in our knowledge of the physiological effects of Ocn in multiple organs and the complex alterations in other hormonal networks induced by Ocn administration. Key steps toward understanding the integrative regulation of energy metabolism by bone would be to identify and characterize the function of the receptor for Ocn. We have discovered a prime candidate for the OcnR, GPRC6A, an amino-acid sensing GPCR that is highly expressed in -cells and is activated by recombinant Ocn in vitro and in vivo. Global ablation of GPRC6A to create OcnR-/- mice results in a phenotype that resembles Ocn-/- mice, including glucose intolerance, reductions in circulating insulin levels, and insulin resistance. Pancreatic islets isolated from OcnR-/- mice exhibit abnormalities of glucose-stimulated insulin secretion and pancreatic islet hypoplasia, suggesting that the OcnR also regulates insulin secretion and -cell mass. Thus, we propose to test the hypotheses that [a] this GPCR is the biologically relevant OcnR and [b] it defines a molecular mechanism for linking bone metabolism with metabolic regulation of insulin secretion and -cell proliferation. In addition, OcnR is also activated by L-arginine and testosterone, and recombinant Ocn regulates testosterone production by the testes, as well as metabolic functions of liver, muscle and fat, suggesting that OcnR may be a multi-liganded receptor connecting multiple endocrine networks. The Specific Aims are to: 1) Test the specific functions of OcnR in pancreatic -cells by tissue-specific loss-of-function experiments in transgenic mouse models and in isolated pancreatic islets ex vivo; 2) Confirm that OcnR mediates the direct effects of recombinant Ocn in pancreatic -cells ; and 3) Determine the binding kinetics of carboxylated and undercarboxylated forms of Ocn for OcnR. Collectively these studies will define the functions of OcnR to integrate physiological networks linking bone, Ocn and other potential ligands to -cell functions and provide knowledge that will help to simplify the complex interdependency between the endocrine functions of bone and hormones secreted by other organs that affect bone and energy metabolism.